Analysis of ordered and disordered protein complexes reveals structural features discriminating between stable and unstable monomers.

Most proteins exist in the cell as multi-component assemblies. However, which proteins need to be present simultaneously in order to perform a given function is frequently unknown. The first step toward this goal would be to predict proteins that can function only when in a complexed form. Here, we propose a scheme to distinguish whether the protein components are ordered (stable) or disordered when separated from their complexed partners. We analyze structural characteristics of several types of complexes, such as natively unstructured proteins, ribosomal proteins, two-state and three-state complexes, and crystal-packing dimers. Our analysis makes use of the fact that natively unstructured proteins, which undergo a disorder-to-order transition upon binding their partner, and stable monomeric proteins, which exist as dimers only in their crystal form, provide examples of two vastly different scenarios. We find that ordered monomers can be distinguished from disordered monomers on the basis of the per-residue surface and interface areas, which are significantly smaller for ordered proteins. With this scale, two-state dimers (where the monomers unfold upon dimer separation) and ribosomal proteins are shown to resemble disordered proteins. On the other hand, crystal-packing dimers, whose monomers are stable in solution, fall into the ordered protein category. While there should be a continuum in the distributions, nevertheless, the per-residue scale measures the confidence in the determination of whether a protein can exist as a stable monomer. Further analysis, focusing on the chemical and contact preferences at the interface, interior and exposed surface areas, reveals that disordered proteins lack a strong hydrophobic core and are composed of highly polar surface area. We discuss the implication of our results for de novo design of stable monomeric proteins and peptides.